The functional receptors responsible for mediating the trophic properties of the nerve growth factor (NGF) family of neurotrophins have been recently identified as members of the trk family of tyrosine protein kinases (Barbacid, 1993). Neurotrophins are growth factors responsible for development and maintenance of neurons. These molecules exert their biological effect through high affinity signaling receptors located on the surface of specific types of neurons.
To date, three different loci, designated trk, trkB and trkC, have been identified. See U.S. Ser. No. 837,814, filed Feb. 25, 1992, which is incorporated herein by reference. The product of the trk proto-oncogene, a 140 kDa cell surface tyrosine protein kinase designated as gp140trk (Martin-Zanca etal., 1989), is the high affinity receptor for NGF (Kaplan et al., 1991; Klein et al., 1991a). The related gp145.sup.trkB tyrosine protein kinase (Klein et al., 1989) serves as the signaling receptor for two related neurotrophins, brain-derived neurotrophic factor (BDNF) (Klein et al., 1991b; Soppet etal., 1991; Squinto et al., 1991) and neurotrophin-4 (NT-4) (Berkemeier et al., 1991, Klein et al., 1992; Ip etal., 1992). Finally, gp145.sup.trkC, a tyrosine protein kinase encoded by the third member of this gene family, trkC, appears to be primarily responsible for mediating the trophic properties of neurotrophin-3 (NT-3) (Lamballe et al., 1991). This gene may also code for additional tyrosine protein kinase isoforms that differ from gp145.sup.trkC by the presence of a small number of amino acid residues within their respective catalytic kinase domains (Lamballe et al., submitted for publication).
The trkB gene is a large (&gt;100 kbp) and complex locus capable of directing the synthesis of multiple transcripts (Klein et al., 1989; 1990a; Middlemas et al., 1991). Some of these transcripts direct the synthesis of the gp145.sup.trkB tyrosine protein kinase receptor. Other transcripts however, code for a second class of trkB receptors that lack a catalytic kinase domain. One of these receptors, gp95.sup.trkB, is abundantly expressed in adult mouse brain (Klein etal., 1990a). Nucleotide sequence analysis of cDNA clones corresponding to these transcripts predicts that gp95.sup.trkB has the same extracellular and transmembrane domains as gp145.sup.trkB, but contains a very short cytoplasmic region of 23 amino acid residues of which the last eleven bear no resemblance to any of the sequences present in gp145.sup.trkB (Klein et al., 1990a). Molecular analysis of rat trkB cDNA clones has identified a second non-catalytic trkB receptor isoform with a predicted sequence identical to that of gp95.sup.trkB except for the presence of a unique nine amino acid-long sequence at its carboxyl terminus (Middlemas et al., 1991).
In situ hybridization analysis has shown that the trkB gene is widely expressed in multiple structures of the central and peripheral nervous systems (Klein et al., 1989; 1990a, b). In the CNS, trkB transcripts have been observed in the cerebral cortex, hippocampus, thalamus, choroid plexus, granular layer of the cerebellum, brain stem and spinal cord. In the PNS, trkB expression is observed in many cranial ganglia including the trigeminal, facial, acoustic, IX/X superior and IX/X inferior ganglia, the retina and ophthalmic nerve, the vestibular system, multiple facial structures, the submaxillary glands and dorsal root ganglia. Analysis of trkB transcripts with probes specific for the catalytic and non-catalytic trkB receptors revealed a rather distinct pattern of expression. For instance, in the adult mouse brain, gp145.sup.trkB transcripts have been detected in the cerebral cortex, thalamus and the pyramidal cell layer of the hippocampus. In contrast, transcripts encoding the non catalytic gp95.sup.trkB receptor appear to be most prominent in structures containing non-neuronal cells such as the ependymal cell layer of the ventricles and the choroid plexus (Klein et al., 1990a).